Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release

用于调节焦亡和细胞因子释放的炎性体和 Gasdermin 信号网络

基本信息

  • 批准号:
    10654563
  • 负责人:
  • 金额:
    $ 188.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-24 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

OVERALL PROGRAM PROJECT: ABSTRACT Cell death pathways have historically been characterized by the proteases that become activated during cell fate decisions. Apoptosis has been defined by initiator and effector caspase activation and, largely due to the reagents available; cell death decisions were initially thought to be binary – caspase-dependent (apoptosis) or caspase-independent (all others). Much like other binary distinctions – like Th1 versus Th2 T cells or M1 versus M2 macrophages, which have undergone substantial expansion in the past decade, cell death decisions and their consequences are now recognized to be much more variables. In fact, even the mechanisms of cell death have been refined. They are no longer categorized by the proteases which activate the cascades but rather, by the effector mechanism. Necroptotic cell death is caused by activation of the pore-forming protein, MLKL. Secondary necrosis is caused by activation of the pore-forming protein, DFNA5 (Gasdermin E/GSDME), and pyroptosis is caused by activation of the pore-forming protein, Gasdermin D (GSDMD) This last category of cell death - pyroptosis - is one of the most immunologically important forms of cell death. Not only does pyroptosis kill the cell, but also GSDMD activation allows the release of IL-1β. This cytokine is among the most important in acute and chronic inflammation. Its secretion is implicated in rare genetic inflammatory diseases such as Familial Mediterranean Fever as well as more common diseases such as myocardial infarction, Alzheimer's disease, Crohn's disease and Ulcerative Colitis, Multiple Sclerosis and many others. With the discovery of the inflammasome in 2002 and its subsequent study, it became clear that the amyloid-like activation of these inflammasome complexes drove pro-IL-1β cleavage and IL-1β release from the cell, but also pyroptosis. Missing from this biochemistry, though, was the cell biology underlying IL-1β release. How is IL- 1β recognized by caspases and other proteases? If IL-1β is not released through a secretory ER-Golgi mechanism, how is trafficked out of the cell? How is this release coordinated with pyroptosis and other regulated cell death pathways that are operative in different populations of immune effector cells. This Program Project aims to utilize cell physiology, biochemistry, structural biology, and mouse and human disease models to unravel these important questions.
总体项目:摘要 细胞死亡途径历来以蛋白酶为特征, 在决定细胞命运的过程中被激活。细胞凋亡由启动子和效应子半胱天冬酶定义 激活,主要是由于可用的试剂;细胞死亡决定最初被认为是 是二元的-半胱天冬酶依赖性(凋亡)或半胱天冬酶非依赖性(所有其他)。很像 其他二元区别-如Th 1与Th 2 T细胞或M1与M2巨噬细胞, 在过去的十年里经历了实质性的扩张,细胞死亡的决定及其 结果现在被认为是更多的变量。事实上,即使是 细胞死亡已经被完善。它们不再被分类为激活蛋白酶 而是通过效应器机制。坏死性细胞死亡是由 孔形成蛋白MLKL的活化。继发性坏死是由于激活了 孔形成蛋白,DFNA 5(Gasdermin E/GSDME),和焦亡是由激活 成孔蛋白Gasdermin D(GSDMD)这是最后一类细胞死亡-细胞凋亡- 是免疫学上最重要的细胞死亡形式之一。尸体自燃不仅能杀死 细胞,而且GSDMD激活允许IL-1β的释放。这种细胞因子是最常见的 在急性和慢性炎症中很重要。它的分泌物与罕见的遗传 炎症性疾病,如家族性地中海热以及更常见的疾病 如心肌梗塞、阿尔茨海默病、克罗恩病和溃疡性结肠炎, 多发性硬化症和许多其他疾病。随着2002年炎性小体的发现及其 随后的研究表明,这些炎性小体的淀粉样激活 复合物驱动IL-1β前体裂解和IL-1β从细胞中释放,但也驱动细胞凋亡。 然而,这种生物化学中缺少的是IL-1β释放背后的细胞生物学。怎么样- 1β被半胱天冬酶和其他蛋白酶识别?如果IL-1β不是通过分泌型 ER-高尔基体机制,是如何被贩运出细胞的?这一版本如何与 细胞凋亡和其他调节性细胞死亡途径,这些途径在不同人群中起作用, 免疫效应细胞本计划项目旨在利用细胞生理学,生物化学, 结构生物学,以及小鼠和人类疾病模型来解开这些重要的问题。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Ras GTPase-activating-like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL-1β release via exosomes.
  • DOI:
    10.15252/embj.2022110780
  • 发表时间:
    2023-01-04
  • 期刊:
  • 影响因子:
    11.4
  • 作者:
    Liao, Yun;Chen, Xing;Miller-Little, William;Wang, Han;Willard, Belinda;Bulek, Katarzyna;Zhao, Junjie;Li, Xiaoxia
  • 通讯作者:
    Li, Xiaoxia
The synthetic oleanane triterpenoid CDDO-2P-Im binds GRP78/BiP to induce unfolded protein response-mediated apoptosis in myeloma.
  • DOI:
    10.1002/1878-0261.13447
  • 发表时间:
    2023-12
  • 期刊:
  • 影响因子:
    6.6
  • 作者:
    Luo, George;Aldridge, Kristin;Chen, Toby;Aslot, Vivek;Kim, Byung-Gyu;Han, Eun Hyang;Singh, Neelima;Li, Sai;Xiao, Tsan Sam;Sporn, Michael B.;Letterio, John J.
  • 通讯作者:
    Letterio, John J.
Partners with a killer: Metabolic signaling promotes inflammatory cell death.
  • DOI:
    10.1016/j.cell.2021.07.036
  • 发表时间:
    2021-08-19
  • 期刊:
  • 影响因子:
    64.5
  • 作者:
    Liu, Zhonghua;Xiao, Tsan Sam
  • 通讯作者:
    Xiao, Tsan Sam
Mechanisms of Gasdermin Recognition by Proteases.
  • DOI:
    10.1016/j.jmb.2021.167274
  • 发表时间:
    2022-02-28
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Liu Z;Busscher BM;Storl-Desmond M;Xiao TS
  • 通讯作者:
    Xiao TS
SARS-CoV-2 ORF3a-Mediated NF-κB Activation Is Not Dependent on TRAF-Binding Sequence.
  • DOI:
    10.3390/v15112229
  • 发表时间:
    2023-11-08
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Busscher BM;Befekadu HB;Liu Z;Xiao TS
  • 通讯作者:
    Xiao TS
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GEORGE R DUBYAK其他文献

GEORGE R DUBYAK的其他文献

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{{ truncateString('GEORGE R DUBYAK', 18)}}的其他基金

The role of Gasdermin E (DFNA5) in bacterial keratitis
Gasdermin E (DFNA5) 在细菌性角膜炎中的作用
  • 批准号:
    10196230
  • 财政年份:
    2021
  • 资助金额:
    $ 188.67万
  • 项目类别:
The role of Gasdermin E (DFNA5) in bacterial keratitis
Gasdermin E (DFNA5) 在细菌性角膜炎中的作用
  • 批准号:
    10393056
  • 财政年份:
    2021
  • 资助金额:
    $ 188.67万
  • 项目类别:
Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release
用于调节焦亡和细胞因子释放的炎性体和 Gasdermin 信号网络
  • 批准号:
    10441352
  • 财政年份:
    2020
  • 资助金额:
    $ 188.67万
  • 项目类别:
Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release
用于调节焦亡和细胞因子释放的炎性体和 Gasdermin 信号网络
  • 批准号:
    10024450
  • 财政年份:
    2020
  • 资助金额:
    $ 188.67万
  • 项目类别:
Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release
用于调节焦亡和细胞因子释放的炎性体和 Gasdermin 信号网络
  • 批准号:
    10223154
  • 财政年份:
    2020
  • 资助金额:
    $ 188.67万
  • 项目类别:
Alternative pathways of gasdermin function and IL-1beta secretion in granulocytic leukocytes
粒细胞白细胞中 Gasdermin 功能和 IL-1β 分泌的替代途径
  • 批准号:
    10024453
  • 财政年份:
    2020
  • 资助金额:
    $ 188.67万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10223155
  • 财政年份:
    2020
  • 资助金额:
    $ 188.67万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10654564
  • 财政年份:
    2020
  • 资助金额:
    $ 188.67万
  • 项目类别:
Alternative pathways of gasdermin function and IL-1beta secretion in granulocytic leukocytes
粒细胞白细胞中 Gasdermin 功能和 IL-1β 分泌的替代途径
  • 批准号:
    10654570
  • 财政年份:
    2020
  • 资助金额:
    $ 188.67万
  • 项目类别:
Alternative pathways of gasdermin function and IL-1beta secretion in granulocytic leukocytes
粒细胞白细胞中 Gasdermin 功能和 IL-1β 分泌的替代途径
  • 批准号:
    10223157
  • 财政年份:
    2020
  • 资助金额:
    $ 188.67万
  • 项目类别:
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